1. Field of Invention
The present invention relates to a method of forming particles. More particularly, the present invention relates to a method of forming particles that involves contacting a solution and a compressed or liquefied gas together at an initial temperature to form a mixture, expanding the mixture at a first temperature to form droplets, and then contacting the droplets and an extracting fluid together at a second temperature to extract solvent from the droplets and thereby obtain particles.
2. Description of Related Art
The majority of particles used in the pharmaceutical industry are produced on a large scale using such techniques as crystallization, precipitation, milling and spray drying. Thermally labile materials are often particulated by techniques such as lyophilization, spray freezing and vacuum drying. Particles can be formed in other ways, such as by phase separation/coacervation, emulsion, high pressure homogenization and supercritical fluid precipitation methods. These various known methods can be used to produce particles in some instances, but there are certain limitations.
Solvent-based methods typically involve precipitation of a solute material from aqueous or organic solutions using anti-solvents (non-solvents). These methods can be practiced on a large industrial scale, but there are inherent problems with the control of particle size distribution and particle morphology. It is particularly difficult to obtain uniform particles having diameters in the lower micron and submicron size range using conventional solvent-based methods. Moreover, solvent-based methods require secondary processes such as filtration, drying, granulation and micronization in order to obtain fine powders from the precipitated product. Another disadvantage of solvent-based methods is that it is usually not possible to engineer particular particles such as, for example, porous, hollow or coated particles, microspheres, and microcapsules. Moreover, there are also significant problems associated with residual solvent in the final product, and with variations between crystallinity and purity from batch to batch.
Milling, mechanical grinding or other mechanical micronization techniques are commonly used to process materials into micro and nanoparticles for oral, respiratory and injectable formulations. These processes can be time-consuming and are generally unsuitable for particulating soft and ductile organic pharmaceuticals. Moreover, since the size distribution of particles processed using these techniques tends to be broad, only a small fraction of the particles produced are in the desired size range after several hours of processing. In addition, the shear forces and temperature generated in milling can produce uncontrollable variations of the solid-state structure of the particles, which may render the formulations unstable or ineffective.
The spray drying technique involves the evaporation of volatile solvents at elevated temperatures, typically between 100° C. and 200° C., using fine nozzles. Although spray drying can be used to produce substantially spherical microparticles, which may be porous or hollow for specific formulations, this technique is problematic for the processing of sensitive or thermally labile materials and crystalline materials. Contact with organic solvents and/or exposure to elevated temperatures can denature some biological materials such as proteins and peptides during processing. Moreover, it is difficult to produce and collect particles having diameters in the submicron range, which results in decreased product yield.
A well-known process for making dry solid formulations of a biomaterial or a thermally labile material is lyophilization. This technique involves freeze-drying, typically of an aqueous solution of the material using high vacuum. Unfortunately this process is very expensive and cannot directly produce particles in the narrow micro—or nanometer size range required for many drug delivery systems.
Another method that suitable for production of particles of thermally labile materials is spray freeze-drying. In this method a solution containing a sensitive material such as a protein, for example, and an excipient is sprayed into a low-temperature liquid, typically liquid nitrogen to form frozen droplets. The frozen droplets are then subsequently lyophilized in order to obtain the particles. Such a process is disclosed in U.S. Pat. No. 6,284,282, which is hereby incorporated by reference in its entirety. However, the low temperature of liquid nitrogen and the corresponding abrupt decrease of temperature or thermal shock during the spraying can degrade some proteins, peptides and other biologically active materials. This can be especially problematic when the spray results in the generation of small particles having a large specific surface area. In addition, the current spray-freezing processes have significant economic disadvantages for large scale-reduction related to handling the liquid nitrogen and excessive costs involved in the second lyophilization stage.
A method that involves spray-freezing a solution into a liquid solvent with consequent liquid-liquid extraction to produce drug-polymer particles is described in U.S. Pat. No. 5,019,400, which is hereby incorporated by reference in its entirety. In this method a solution containing an active material and a polymer is sprayed into a liquid non-solvent such as ethanol or layer of inert liquefied gas such as liquid nitrogen overlaying the layer of frozen liquid non-solvent. The frozen solution droplets undergo liquid-liquid extraction during a thawing cycle involving the droplets and the liquid non-solvent. The inert liquefied gas is then evaporated after freezing of droplets of polymer solution. The major disadvantage of this method is related to the residual solvent left in the product after extraction, which requires a separate filtering of particles, washing and consequent vacuum-evaporation or other purification stages. In addition, the method disclosed is only suitable for the production of relatively large particles with size of tens of micrometers, due to low dispersion efficiency of ultrasonic or gas-blowing nozzles.
A method that involves spray-freezing a solution into a freezing zone created by a spray of liquid nitrogen or other liquefied gas such as liquid argon and helium with an initial temperature sufficiently low to freeze the solution droplets is described in U.S. Pat. No. 6,358,443, which is hereby incorporated by reference in its entirety. Similar to the previously discussed technique, this method has a disadvantage of handling liquefied low temperature gases on large scale. Additional problems include the unwanted incorporation of residual solvent in the resulting particles, and the inability to produce small particles (i.e., having diameters less than tens of micrometers) due to the low dispersion efficiency of the nozzles used.
Vacuum-assisted freezing is another process for the preparation of small particles of temperature-sensitive compounds. In vacuum-assisted freezing, a solution is introduced into an evacuated chamber in the form of a spray. Droplets of the spray are at a sufficiently low temperature to freeze at the vacuum pressure inside the chamber. The frozen solvent is sublimated from the collected frozen droplets. Such a procedure is disclosed in U.S. Pat. No. 5,727,333, which is hereby incorporated by reference in its entirety. Unfortunately, the requirement of a vacuum limits the throughput of the solution and prevents control over the particle size, in particular, for particles in the lower micron size range. Furthermore, the cost of the process is similar to or higher than the cost of the Iyophilization process. All these factors hinder the industrial applicability of this process.
Methods involving supercritical fluid (SCF) precipitation facilitate particle formation at near-ambient temperatures and eliminate a need for a liquid-vapor interface. However, SCF precipitation has disadvantages because water and carbon dioxide (CO2) are poorly miscible fluids, and therefore any precipitation technique using CO2 and an aqueous solution requires the addition of an organic co-solvent to increase the solubility of water in CO2. Many biologically active materials are irreversibly degraded as a result of contacting the organic co-solvent. Precipitation of uniform size particles for certain materials is difficult using supercritical fluids because of the same limitations as for the liquid solution precipitation process. And, SCF methods involve high-pressure equipment and therefore involve relatively high capital and running costs.
For the reasons thus stated, there exists a need for a particle production technique that would be capable of processing different drug and excipient materials, including thermally labile, water-soluble or water insoluble substances, into micro and nanoparticles, particles of respiratory size range (1–5 μm), porous particles, and/or composite drug-excipient particles. Such a technique would preferably exhibit sufficient processing efficiency to be economically suitable for use in the large-scale industrial production of particles. Further, it would be advantageous for such a technique to offer flexibility in terms of particle solid-state properties such as size and morphology.